Heteroaromatic quinuclidinenes, their use and preparation

ABSTRACT

The invention relates to novel compounds of general formula (I), wherein R is a group of general formula (II) or (III), where X 1  represents oxygen or sulphur and Y 1  and Z 1  both represent carbon, or X 1  represents oxygen and one of Y 1  and Z 1  represents nitrogen and the other represents carbon, or X 1  represents sulphur, Y 1  represents nitrogen and Z 1  represents carbon; one of X 2 , Y 2  and Z 2  represents oxygen or sulphur and the other two both represent carbon or one represents nitrogen and the other represents carbon, and the dotted line in formula (III) represents an optional additional carbon-carbon or carbon-nitrogen bond; A 1 , A 2 , A 3  and A 4  each represent carbon or, when one of X 2 , Y 2  and Z 2  represents oxygen or sulphur and the other two both represent carbon, one or two of A 1 , A 2 , A 3  and A 4  may represent nitrogen and the others carbon; and R 1  to R 5  are as defined in the description. The compounds of formula (I) can be used for treating diseases related to muscarinic receptor function.

This application is a 371 of PCT/SE93/00415 filed May 11, 1993.

FIELD OF THE INVENTION

The present invention relates to novel chemical compounds havingactivity at central and peripheral nervous systems, pharmaceuticalcompositions containing them, the use of the compounds for preparingmedicaments, and processes for their preparation.

BACKGROUND OF THE INVENTION AND PRIOR ART

Acetylcholine is one of the most important neurotransmitters in thecentral and peripheral nervous systems. Receptors mediating the actionsof acetylcholine are subdivided into nicotine-like and muscarine-like,based on the action of particular agonists and antagonists.

The cholinergic receptors in the central nervous system of mammals aremainly muscarinic. Cholinergic deficiencies in the central nervoussystem have been implicated in several neurological and mentalillnesses, such as Alzheimer's disease and senile dementia of theAlzheimer type. Muscarinic agonists capable of increasing thecholinergic transmission in the brain, particularily in the cortex, maytherefore be of therapeutic value in the treatment of Alzheimer'sdisease and other diseases related to impairment of the cholinergicnervous system.

Muscarinic receptors in the peripheral nervous system mediate theactions of acetylcholine at parasympathetic postganglionic neuroeffectorjunctions. Evidence also indicate that muscarinic receptors can modulatetransmission in autonomic ganglia. Muscarinic presynaptic receptorsregulating transmitter release are present in the central as well asperipheral nervous system.

Stimulation of postsynaptic peripheral receptors generate numerousphysiological responses, including smooth muscle contraction, secretionby various glands, bronchoconstriction, relaxation of vascular smoothmuscles, decrease in the cardiac rate and force of contraction.

Among the various compounds which are described in the prior art ashaving activity on muscarinic receptors are, for instance, derivativesbased upon azabicyclic alkanes, particularly azabicyclo[2.2.2]octane(quinuclidine) and azabicyclo[2.2.1]heptane derivatives. Thus, forexample, EP-A-301 729 discloses oxadiazolyl-substituted quinuclidine andquinuclidinene compounds which are potent muscarinic agonists.

EP-A-307 142 discloses oxathiazolyl-substituted quinuclidine andquinuclidinene compounds having potent muscarinic agonist activity.

EP-A-307 141 discloses oxazolyl- and thiazolyl-substituted quinuclidinesand quinuclidinenes which stimulate muscarinic acetylcholine receptors.

EP-A-287 356 discloses oxazolyl-substituted azabicyclo[3.2.1]octaneswhich enhance acetylcholin function via an action at muscarinicreceptors.

EP-A-363 085 discloses azabicyclo[2.2.2]octanes and -[2.2.1]heptanessubstituted by oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, furyl,triazolyl or tetrazolyl groups, which compounds enhance acetylcholinefunction via muscarinic receptors.

EP-A-316 718 discloses oxadiazolyl- andisoxazolyl-8-azabicyclo[3.2.1]oct-2-enes having muscarinic cholinergicreceptor antagonistic activity.

EP-A-328 200 discloses methylindolyl-oxadiazolyl-quinuclidines having5-HT₃ receptor activity.

EP-A-450 345 discloses 3-(3-indolyl)-quinuclidines and quinuclidineneswhich antagonize the activity of serotonin on 5-HT₃ receptors.

EP-A-261 763 discloses oxadiazolyl- and thia(dia)zolyl-quinuclidineswhich enhance acetylcholine function via an action at muscarinicreceptors.

EP-A-427 390 disclose pyrazol-, triazol- and tetrazol-quinuclidines and-quinuclidinenes which enhance acetylcholine function via muscarinicreceptors.

J. Med. Chem. 33 (1991) 1128-1138 discloses a series of heterocyclicsubstituted quinuclidines spanning the activity range from efficaciousmuscarinic agonists, through partial agonists, to muscarinicantagonists. Among the substituent heterocycles are oxazolyl, furyl,methylfuryl and methyloxazolyl. The specific compounds3-(5-methyl-2-furyl)quinuclidinene, 3-(4-methyl-2-furyl)quinuclidineneand 3-(2-furyl)quinuclidinene are only disclosed as non-isolatedintermediates in the preparation of the corresponding quinuclidines.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a class of novelsubstituted quinuclidinene derivatives which block or stimulatemuscarinic acetylcholine receptors, centrally or peripherally, andtherefore are of potential use for the treatment of diseases wherecholinergic receptors are involved.

Accordingly, the present invention provides novel compounds of thegeneral Formula I: ##STR2## wherein R is a group of the general FormulaII or III: ##STR3## where X¹ represents oxygen or sulphur and Y¹ and Z¹both represent carbon, or X¹ represents oxygen and one of Y¹ and Z¹represents nitrogen and the other represents carbon, or X¹ representssulphur, Y¹ represents nitrogen and Z¹ represents carbon;

one of X², Y² and Z² represents oxygen or sulphur and the other two bothrepresent carbon or one represents nitrogen and the other representscarbon, and the dotted line in Formula III represents an optionaladditional carbon-carbon or carbon-nitrogen bond;

A¹, A², A³ and A⁴ each represent carbon or, when one of X², Y² and Z²represents oxygen or sulphur and the other two both represent carbon,one or two of A¹, A², A³ and A⁴ may represent nitrogen and the otherscarbon;

R¹, R² and R³ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, C₁₋₁₀ alkoxy, C₂₋₁₀alkenyloxy, C₂₋₁₀ alkynyloxy, C₃₋₁₀ cycloalkyloxy, C₅₋₁₀cycloalkenyloxy, C₄₋₁₀ cycloalkylalkoxy, C₆₋₁₀ cycloalkylalkenyloxy,hydroxy, hydroxy-C₁₋₁₀ alkyl, or (CH₂)_(n) Ar, where Ar is optionallysubstituted aryl or heteroaryl, the latter containing 1 to 3 heteroatomsselected from oxygen, sulphur and nitrogen, and n is an integer 0 to 10;and

R⁴ and R⁵ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, halogen or (CH_(m))_(n) B,wherein (CH_(m))_(n), in which n is as defined above and m independentlyis an integer 0 to 2, represents a bond or a straight or branched,saturated or unsaturated hydrocarbon chain and B represents Ar (asdefined above), COR⁶, COOR⁶, CON(R⁶)₂, N(R⁶)₂, OR⁶, CN, NO₂, C=NOR⁶,OCOR⁶, N(R⁶)COR⁶, C(R⁶)₂ OR⁶, OCOC(OH)(R⁶)₂ or trifluoromethyl, where R⁶independently represents hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl,C₆₋₁₀ cycloalkylalkenyl, (CH₂)_(n) Ar or a bi- or tricyclic ring systemcomprising 0 to 3 ring hetero atoms, wherein Ar and n are as definedabove; or

R⁴ and R⁵ are interconnected to complete a saturated or unsaturated ringwhich may contain 1 or 2 hetero atoms;

with the proviso that when R represents a group of Formula II and R¹, R²and R³ each are hydrogen, R is other than 2-furyl, 4-methyl-2-furyl and5-methyl-2-furyl; and physiologically acceptable salts thereof.

The invention also provides a pharmaceutical composition comprising acompound of the general Formula IA: ##STR4## wherein R¹, R² and R³ areas defined above, and R_(a) is as defined above for R and additionallymay represent 2-furyl, 4-methyl-2-furyl and 5-methyl-2-furyl also whenR¹, R² and R³ are hydrogen.

The invention additionally provides the use of the compounds of FormulaIA above for the manufacture of a medicament for the prevention ortreatment of a disease or disorder related to muscarinic receptorfunction.

The invention further provides a therapeutical method which comprisesadministering a compound of Formula IA to a subject in need thereof.

Processes for the production of the compounds of Formula I as well asintermediate products used therein are also included in the invention aswill be described further below.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I and IA above, C₁₋₁₀ alkyl and C₁₋₁₀ alkoxyare straight or branched and are preferably C₁₋₆ alkyl and C₁₋₆ alkoxy,respectively, and more preferably C₁₋₄ alkyl and C₁₋₄ alkoxy,respectively. Illustrative examples include methyl, ethyl, n-propyl,iso-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the correspondingalkoxy groups.

C₂₋₁₀ alkenyl and C₂₋₁₀ alkenyloxy are straight or branched and arepreferably C₂₋₆ alkenyl and C₂₋₁₀ alkenyloxy, respectively, and morepreferably C₂₋₄ alkenyl and C₂₋₄ alkenyloxy, respectively. Illustrativeexamples include ethenyl, 2-propenyl, 3-butenyl, 1-methyl-2-propenyl,2-pentenyl, 2-ethyl-3-butenyl and 4-hexenyl, and the correspondingalkenyloxy groups.

C₂₋₁₀ alkynyl and C₂₋₁₀ alkynyloxy are straight or branched and arepreferably C₂₋₆ alkynyl and C₃₋₆ alkynyloxy, respectively, and morepreferably C₂₋₄ alkynyl and C₃₋₄ alkynyloxy, respectively. Illustrativeexamples include ethynyl, 2-propynyl, 1-methyl-2-propynyl, 3-butynyl,1-ethyl-2-propynyl, 1-methyl-3-butynyl, 4-pentynyl, and 5-hexynyl, andthe corresponding alkynyloxy groups.

C₃₋₁₀ cycloalkyl and C₃₋₁₀ cycloalkyloxy are preferably C₃₋₈ cycloalkyland C₃₋₈ cycloalkyloxy, respectively, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the corresponding cycloalkyloxy groups.Also alkyl-substituted carbocyclic rings are included, for example,methyl-, dimethyl- and ethylcyclohexyl.

C₅₋₁₀ cycloalkenyl and C₅₋₁₀ cycloalkenyloxy are preferably C₃₋₈cycloalkenyl and C₃₋₈ cycloalkenyloxy, respectively, such ascyclopentenyl, cyclohexenyl, methyl-, dimethyl- and ethylcyclohexenyl,and the corresponding cycloalkenyloxy groups.

Exemplary of C₄₋₁₀ cycloalkylalkyl and C₄₋₁₀ cycloalkylalkoxy arecyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,and the corresponding cycloalkylalkoxy groups.

Exemplary of C₆₋₁₀ cycloalkylalkenyl and C₆₋₁₀ cycloalkylalkenyloxy,respectively, are cyclopentylethenyl, cyclopentylpropenyl,cyclohexylethenyl and cyclohexylpropenyl, and the correspondingcycloalkylalkenyloxy groups.

The term halogen includes fluorine, chlorine, bromine and iodine.

Aryl is preferably phenyl or naphthyl, more preferably phenyl.

Heteroaryl may, for example, be monocyclic, such as tiophene, furan,pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,triazole, pyridine, pyrazine, pyrimidine, pyridazine, or bicyclic, suchas benzofuran, isobenzofuran, benzothiazole, benzothiophene, indole,isoindole, oxadiazole, benzoxazole.

Phenyl and heteroaryl may be substituted by one or more substituentsselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, and the groups definedfor B above except Ar.

R¹, R² and R³ may each independently be bound in any one of positions 2,4, 5, 6, 7 and 8, and, except when representing hydrogen, also inposition 1 of the quinuclidinene ring. Preferably, R¹, R² and R³ areeach hydrogen (i.e. the quinuclidinene ring is only substituted inposition 3).

Exemplary of groups of Formulae II and III are: ##STR5##

The groups of Formulae II and III may be connected to the 3-position ofthe quiniclidinene ring via any carbon atom of the five-memberedheterocyclic ring.

R⁴ and R⁵ may be bound to any carbon atom of the heterocyclic ring orring system, except the position of connection to the quinuclidinenering.

Preferably, R⁴ and R⁵ independently are hydrogen, C₁₋₁₀ alkyl,optionally substituted aryl or heteroaryl or the group (CH_(m))_(n) B asdefined above. In a preferred group of compounds, one of R⁴ and R⁵represents hydrogen and the other C₁₋₆ alkyl or optionally substitutedphenyl.

n is preferably 0-6, more preferably 0-3.

B is preferably N(R⁶)₂, OR⁶, C═NOH, OCOR⁶, N(R⁶)COR⁶ or C(R⁶)₂ OR⁶.

The straight or branched, saturated or unsaturated hydrocarbon chain(CH_(m))_(n) is preferably unsaturated, containing one or more, such asone or two, double and/or triple bonds. Preferably, the hydrocarbonchain has up to six carbon atoms. Exemplary of the group (CH_(m))_(n)are methylene, allylene, ethylene, vinylene, acetylene, etc.

When R⁶ represents a bi- or tricyclic ring system, at least one of therings may be heterocyclic. For example, a tricyclic ring system maycomprise a phenyl ring flanked by two heterocyclic rings, a heterocyclicring fused to naphthyl, or a heterocyclic ring flanked by two phenylrings. Preferably, the ring system is bicyclic, for example consistingof naphthyl or phenyl fused to a heterocyclic ring, or of two fusedheterocyclic rings. Exemplary heterocycles are those mentioned above forthe definition of heteroaryl.

Preferably, R⁶ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or optionally substitutedphenyl or furyl, more preferably C₂₋₆ alkynyl or optionally substitutedphenyl.

When R⁴ and R⁵ are interconnected to form, together with part of theheteroaryl group to which they are bound, a saturated or unsaturated,optionally heterocyclic ring, such a ring may be a C₃₋₁₀ cycloalkyl,C₃₋₁₀ cycloalkenyl or an aryl or heteroaryl ring, such as a cyclohexane,benzene, piperidine, pyridazine or pyridine ring fused to the heteroarylgroup of Formula II or III above.

In a preferred subgroup of the compounds of Formula I, R¹, R² and R³ areeach hydrogen and R is an optionally substituted furyl, thienyl orbenzofuryl ring.

Due to the basic nitrogen of the quinuclidinenyl ring, the compounds ofFormula I may form addition salts with pharmaceutically andphysiologically acceptable organic or inorganic acids, and the inventioncomprises the free bases as well as the salts thereof. Examples ofaddition salt forming acids are oxalic acid, fumaric acid, malic acid,maleic acid, succinic acid, methane sulfonic acid, acetic acid, benzoicacid, hydrochloric acid, sulphuric acid, phosphoric acid, and the like.When one of R¹, R² or R³ (other than hydrogen) is bound to the nitrogenatom of the quinuclidinene ring, the compounds of Formula I formquaternary amine salts, which salts are likewise encompassed by theinvention.

When the novel compounds can be in the form of optical isomers, theinvention comprises the racemic mixture as well as the individualenantiomers as such.

Specific compounds within the scope of the present invention include,but are not limited to the following:

3-(2-furyl)quinuclidin-2-ene

3-(3-furyl)quinuclidin-2-ene

3-(5-ethyl-2-furyl)quinuclidin-2-ene

3-(3-bromo-2-furyl)quinuclidin-2-ene

3-(3-thienyl)quinuclidin-2-ene

3-(2-thienyl)quinuclidin-2-ene

3-(5-methyl-2-furyl)quinuclidin-2-ene

3-(3-phenyl-2-furyl)quinuclidin-2-ene

3-(5-methyl-2-thienyl)quinuclidin-2-ene

3-(5-phenyl-2-furyl)quinuclidin-2-ene

3-(3-methyl-2-furyl)quinuclidin-2-ene

3-(5-methoxycarbonyl-2-furyl)-quinuclidin-2-ene

3-(2-benzofuryl)quinuclidin-2-ene

3-(5-bromo-2-benzofuryl)-quinuclidin-2-ene

3-(2-benzothienyl)quinuclidin-2-ene

3-(3-benzothienyl)quinuclidin-2-ene

3-(benzothiazol-2-yl)quinuclidin-2-ene

3-[5-(N-phenylcarbamoyl)-2-furyl]-quinuclidin-2-ene

3-(benzoxazol-2-yl)quinuclidin-2-ene

3-(5-butyl-2-furyl)quinuclidin-2-ene

3-(5-acetyl-2-furyl)quinuclidin-2-ene

3-(4-acetyl-2-furyl)quinuclidin-2-ene

3-(4-phenyl-2-furyl)quinuclidin-2-ene

3-(5-acetyl-2-thienyl)quinuclidin-2-ene

3-(5-formyl-2-thienyl)quinuclidin-2-ene

3-(5-formyl-7-methoxy-2-benzofuryl)quinuclidin-2-ene

3-(5-hydroxymethyl-7-methoxy-2-benzofuryl)quinuclidin-2-ene

3-(7-hydroxymethyl-5-iodo-2-benzofuryl)quinuclidin-2-ene

3-(7-iodo-5-nitro-2-benzofuryl)quinuclidin-2-ene

3-(5-cyano-7-iodo-2-benzofuryl)quinuclidin-2-ene.

The compounds of the present invention having antimuscarinic activityare useful for the treatment of extrapyramidal motor disorders,Parkinsonism, disorders affecting the parasympathetic nervous system,spastic states affecting the gastrointestinal channel, gall bladder andkidneys, ulcus ventriculi and duodeni, hypersecretion, bradycardia,hyperhidrosis, disorders affecting the pulmonary system, and fortreatment of disorders of the urinary bladder such as motor urgeincontinence.

Compounds of the present invention being agonists, and/or partialagonists having specific presynaptic antimuscarinic activity anddisplaying central nervous system activity, may potentially be used forthe treatment of memory dysfunctions, senile dementia, Alzheimer'sdisease, schizophrenia, Huntington's chorea, tardive dyskinesia, and asanalgesics for the treatment of pain, and as sleep aids.

Compounds of the present invention being agonists may potentially beused for treatment of disorders affecting the parasympathetic nervoussystem such as urinary retention, atony of the gastrointestinal channel,kidneys, and gall bladder, and glaucoma.

The compounds of the general Formula IA above, in the form of free basesor salts of acceptable organic or inorganic acids, can be brought intosuitable galenic forms, such as formulations for oral, transdermal, orintranasal use, and for injection, or the like, in accordance withconventional pharmaceutical procedures. Such formulations comprise theactive compound in association with pharmaceutically acceptablecarriers. The carriers may be any inert material, organic or inorganic,suitable for enteral, percutaneous or parenteral administration, such aswater, gelatin, gum arabicum, lactose, cellulose, starch, sodium starchglycolate, cyclodextrins, calcium hydrogen phosphate, magnesiumstearate, talcum, colloidal silicon dioxide, stabilizers, wettingagents, emulsifiers, flavouring agents, buffers, and the like.

The pharmaceutical formulations according to the invention comprisesolid as well as liquid dosage forms, such as tablets, capsules,powders, syrups, elixirs, depots, sterile solutions, suspensions oremulsions, and the like for oral and parenteral administration.

The dosage of the compound of Formula IA to be administered will, ofcourse, depend on the potency of the selected specific compound, themode of administration, the age and weight of the patient, the severityof the condition to be treated, and the like. The daily dosage may, forexample, be from about 0.001 mg to about 25 mg per kilo of body weight,administered in one or more doses. The compositions of the invention arepreferably formulated in a unit dosage form, containing, for example,about 0.05 to about 500 mg of the active ingredient.

The compounds according to the invention can be prepared according toper se conventional methods using starting materials which are eithercommercially available, or can be prepared by methods known from theliterature, or as described herein. More particularly, the presentinvention provides processes for the preparation of the novel compoundsof Formula I, which processes comprise:

(a) dehydrating a compound of the general Formula IV: ##STR6## whereinR, R¹, R² and R³ are as defined in claim 1; or (b) for the preparationof a compound of Formula I wherein R⁴ and R⁵ are as defined in claim 1except that R⁵ is other than hydrogen, reacting, in the presence of ametal catalyst, a compound of the general Formula V or VI: ##STR7## witha compound R⁸ -D, wherein X¹, Y¹, Z¹, X², Y², Z² and R⁴ are as definedin claim 1, D is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀cycloalkylalkenyl, (CH₂)_(n) Ar or (CH_(m))_(n) B, where Ar, n, m and Bare as defined above, and one of R⁷ and R⁸ represents halogen, triflateor mesylate, preferably halogen or triflate, and the other represents agroup selected from Sn(Alk)₃, Si(Alk)₃, ZnHal, Al(R⁹)₂, TlX₂, HgX andB(OR⁹)₂, where Alk is alkyl of from 1 to 10 carbon atoms, Hal ishalogen, X is halogen, acetate or trifluoroacetate, and R⁹ is hydrogenor Alk; or R⁷ represents halogen, triflate or mesylate, preferablyhalogen or triflate, and R⁸ -D is C₂₋₁₀ alk-1-yn;

c) for the preparation of a compound of Formula I wherein R⁴ and R⁵ areas defined in claim 1 except that R⁵ is other than hydrogen, generatingthe carbanion of a compound of the general Formula VII or VIII: ##STR8##wherein X¹, Y¹, Z¹, X², Y², Z² and R⁴ are as defined in claim 1, and R¹⁰represents hydrogen or halogen, and reacting the carbanion formed withan electrophilic reagent capable of forming the desired substituent R⁵ ;

(d) reacting, in the presence of a metal catalyst, a compound of thegeneral Formula IX: ##STR9## with a compound R--E, wherein R, R¹, R² andR³ are as defined in claim 1, and one of R¹¹ and E represents halogen,triflate or mesylate, preferably halogen or triflate, and the otherrepresents a group selected from Sn(Alk)₃, Si(Alk)₃, ZnHal, Al(R⁹)₂,TlX₂, HgX, and B(OR⁹)₂, where Alk is alkyl of from 1 to 10 carbon atoms,Hal is halogen, X is halogen, acetate or trifluoroacetate and R⁹ ishydrogen or Alk;

(e) for the preparation of compounds of Formula I, wherein R is a groupof Formula III, in which A¹ to A⁴ each are carbon or one or two of A¹ toA⁴ are nitrogen and the others are carbon, X² is oxygen or sulphur andY² and Z² both are carbon, reacting a compound or intermediate of thegeneral Formula X: ##STR10## wherein R¹, R² and R³ are as defined inclaim 1, with a compound of the general Formula XI: ##STR11## wherein R⁴and R⁵ are as defined in claim 1, Hal represents halogen, X^(2a)represents oxygen or sulphur, and A^(1a) to A^(4a) each represent carbonor one or two of of A^(1a) to A^(4a) represent nitrogen and the othersrepresent carbon;

(f) for the preparation of compounds of Formula I, wherein R is a groupformula III, in which A¹ to A⁴ each are carbon or one or two of A¹ to A⁴are nitrogen and the others are carbon, X² is oxygen or sulphur and Y²and Z² both are carbon, reacting a compound or intermediate of thegeneral Formula XII: ##STR12## wherein R¹, R² and R³ are as defined inclaim 1, with a compound of Formula XI as defined in process e) above,and then dehydrating the product formed;

(g) in a compound of Formula I, converting a group R⁴ or R⁵ into anothergroup R⁴ or R⁵ ;

and, if desired, forming a physiologically acceptable salt with anorganic or inorganic acid.

The dehydration in processes a) and f) may be performed byacid-catalyzed dehydration, usually at elevated temperature, e.g. up to250° C. Suitable acids are, e.g., formic and methanesulfonic acids.Alternatively, the hydroxy group may be removed by halogen substitutionand subsequent elimination thereof. Chlorination may, for example, beeffected by treatment with phosphorus oxychloride in the presence oftriethylamine, or with thionyl chloride followed by e.g.diazabicyclononane (DBN) treatment.

The starting compounds of Formula IV in process a), except the compoundswherein R¹, R², and R³ each are hydrogen and R is 2-furyl,4-methyl-2-furyl or 5-methyl-2-furyl, are novel and also form part ofthe present invention.

The compounds of Formula IV may be prepared by reacting 3-quinuclidinonewith the anion of the heterocycle corresponding to the group R inFormula IV in a nucleophilic carbonyl addition reaction. Suchheterocyclic anion may be prepared by treating the heterocycle or ahalogen-substituted heterocycle with n-butyl lithium or lithiumdiisopropylamide in a solvent, such as tetrahydrofuran or diethylether,at reduced temperature, e.g. in the range -100° C. to 0° C.

In process b), when R⁷ is halogen, such as bromine, triflate ormesylate, a desired alkyl, alkenyl, alkynyl, aryl or heteroarylsubstituent may be introduced by metal-catalyzed coupling (e.g. Pd, Ni)of the compound of Formula V or VI with (i) e.g. the correspondingtetralkyl tin, alkenyltrialkyl tin, alkynyltrialkyl tin, aryltrialkyltin, heteroaryltrialkyl tin or alkyn reagent, or (ii) e.g. thecorresponding aryl or heteroaryl boronic acid, or aryl orheteroaryldialkyl boronic acid ester.

When R⁷ is Sn(Alk)₃, Si(Alk)₃, ZnHal, Al(R⁹)₂, TlX₂, or HgX, a desiredaryl or heteroaryl substituent may be introduced by metal-catalyzedcoupling (e.g. Pd, Ni) of the compound of Formula V or VI with thecorresponding aryl halogen, triflate or mesylate, or heteroaryl halogen,triflate or mesylate compound.

A trialkylstannyl compound V or VI (R⁷ is Sn(Alk)₃) may, for example, beprepared by lithiation of the corresponding R⁷ -unsubstituted, and whennecessary halogenated, compound in a solvent, such as tetrahydrofuran ordiethyl ether, at reduced temperature and quenching of the anion withtrialkyltin chloride.

When R⁷ in Formula V or VI is B(OH)₂ or B(OAlk)₂, a desired aryl orheteroaryl substituent may be introduced by metal-catalyzed coupling(e.g. Pd, Ni) of the compound of Formula V or VI with the correspondingaryl halogen, triflate or mesylate, or heteroaryl halogen, triflate ormesylate compound.

A dialkylboronic ester compound V or VI (R⁷ is B(OAlk)₂) may, forexample, be prepared by lithiation of the corresponding R⁷-unsubstituted compound with n-butyl lithium in a solvent, such astetrahydrofuran or diethyl ether, at reduced temperature, and quenchingthe anion with trialkyl borate.

In process c), the carbanion of the compound of Formula VII or VIII maybe generated by O-lithiation, halogen-metal exchange or generation of aGrignard reagent. The electrophilic reagent used to quench the carbanionto produce the final product is selected depending on the desiredsubstitution, and may e.g. be an aldehyde or a ketone (forming ahydroxyalkyl, -aryl or -heteroaryl substituent), a nitrile or acidchloride (forming a keto substituent), an alkyl halide (forming an alkylsubstituent), or molecular halogen (forming a halogen substituent).

The starting Compounds of Formula IX in process d) in which R¹¹ isSn(Alk)₃, Si(Alk)₃, ZnHal, Al(R⁹)₂, TlX₂, HgX or B(OR⁹)₂, may beprepared by reacting 3-quinuclidinone with2,4,6-triisopropylbenzenesulfonyl hydrazide to give3-(2,4,6-triisopropylbenzenesulfonyl hydrazone)quinuclidine. The lattercompound is then treated with two equivalents of n-butyl lithium atreduced temperature in a solvent, such as TMEDA/hexane ortetrahydrofuran, and subsequently quenched with the appropriate reagent,such as with trialkyltin chloride to give3-trialkylstannyl-quinuclidin-2-ene, or with trialkyl borate to give the3-alkylboronic acid ester of the quinuclidine-2-ene or the 3-boronicacid of the quinuclidin-2-ene.

The starting compounds of Formula IX in process d) in which R¹¹ ishalogen, may be prepared by reacting the 3-quinuclidinone with2,4,6-triisopropylbenzenesulfonyl hydrazide to give3-(2,4,6-triisopropylbenzenesulfonyl-hydrazone)-quinuclidine. Thiscompound is then treated with 2 equivalents of n-butyllithium at reducedtemperature in a solvent, such as TMEDA/hexane or THF, and subsequentlyquenched with an electrophilic halogen reagent (such as Br₂, I₂ orN-bromosuccinimide (NBS)) to give the 3-halogeno-quinuclidin-2-ene.

Processes e) and f) may be performed at elevated temperature in asolvent, such as pyridine. The starting compounds of Formula XI may beprepared as described by Grob et al, Helv. Chim. Acta, 1963, pages2658-2666.

The invention will now be further illustrated by the followingnon-limiting examples.

GENERAL

Routine ¹ H and ¹³ C NMR spectra were recorded at 90 and 22.5 MHz,respectively, on a JEOL FX 90Q spectrometer and were referenced tointernal tetramethylsilane. All NMR spectra were in accordance with theassigned structures.

Melting points (uncorrected) were determined in open glass capillarieson a Thomas-Hoover apparatus.

Capillary GC was performed on a Carlo Erba 6000, by use of an SE 52column (25 m) or DB5 column (25 m), equipped with a flame ionizationdetector (FID-40) and a Milton Roy CI-10B integrator. The elementalanalyses, (C, H and N), which were within ±0.4% of the theoreticalvalues, were performed by Mikro Kemi AB, Uppsala, Sweden.

EXAMPLE 1 3-(2-Thienyl)quinuclidin-3-ol, 0.5 Fumarate

A solution of n-butyllithium in hexane (17.6 mL, 1.35M, 23.7 mmol) wasadded dropwise to a stirred solution of thiophene (2.30 mL, 28.7 mmol)in dry ether (30 mL) at 0° C. A solution of 3-quinuclidinone (2.71 g,21.6 mmol) in dry ether (30 mL) was added dropwise after standing for 2hours and the mixture was allowed to warm to room temperature over 10hours. The mixture was quenched with saturated ammonium chloride (10 mL,added dropwise), poured into 2M hydrochloric acid and washed with ether.The aqueous layer was basified with 5M sodium hydroxide; the product wasextracted with ether, dried over potassium carbonate and concentrated invacuo. Column chromatography on alumina with gradient elution [CHCl₃→CHCl₃ /MeOH (95:5)] gave 4.03 g (89%) of the product, which wasconverted to the fumarate and recrystallized from Et₂ O/MeOH/acetone: mp208°-210° C.; Rf 0.25 in CHCl₃ /MeOH (95:5) on alumina.

C₁₁ H₁₅ NOS.0.5C₄ H₄ O₄ requires: C, 58.4; H, 6.4; N, 5.2. Found: C,58.2; H, 6.3; N, 5.1.

EXAMPLE 2 3-(2-Furyl)quinuclidin-3-ol, Fumarate

By essentially following the procedure in Example 1, substituting furanfor thiophene, the title compound was prepared with a yield of 73%; mp176.5°-177.5° C.

C₁₁ H₁₅ NO₂.C₄ H₄ O₄ requires: C, 58.2; H, 6.2; N, 4.5. Found: C, 58.3;H, 6.2; N, 4.5.

EXAMPLE 3 3-(3-Furyl)quinuclidin-3-ol, 0.5 Fumarate

A solution of n-butyllithium in hexane (14.2 mL, 1.5M, 21.3 mmol) wasadded dropwise to a solution of 3-bromofuran (2.2 mL, 23.9 mmol) in dryether (40 mL) at -75° C. over 10 min. After 5 min., a solution of3-quinuclidinone (2.66 g, 21.2 mmol) in dry ether (20 mL) was added, andthe mixture was stirred at -75° C. for 4 hours. A solution of saturatedaqueous ammonium chloride (1.5 mL) was added dropwise at -70° C., andthe mixture was poured into 2.5M aqueous HCl and washed with ether. Theaqueous layer was basified with 5M aqueous NaOH; the product wasextracted with ether, dried (K₂ CO₃), filtered, and concentrated invacuo. Column chromatography on alumina, gradient eluted with CHCl₃→CHCl₃ /MeOH (95:5), yielded 2.01 g (49%) of pure3-(3-furyl)quinuclidin-3-ol, which was converted into the fumarate andrecrystallized from acetone/MeOH; mp 207°-209° C.; Rf 0.21 in CHCl₃/MeOH on alumina. C₁₁ H₁₅ NO₂.0.5C₄ H₄ O₄ requires: C, 62.1; H, 6.8; N,5.5. Found: C, 61.9; H, 6.9; N, 5.6.

EXAMPLE 4 3-(5-Methyl-2-furyl)quinuclidin-3-ol, 0.5 Fumarate

By essentially following the procedure in Example 1, substituting2-methylfuran for thiophene, the title compound was prepared with ayield of 82%; mp 177.5°-178.5° C. C₁₂ H₁₇ NO₂.0.5C₄ H₄ O₄ requires: C,63.4; H, 7.2; N, 5.3. Found: C, 63.3; H, 7.2; N, 5.2.

EXAMPLE 5 3-(3-Thienyl)quinuclidin-3-ol, 0.5 Fumarate

By essentially following the procedure in Example 3, substituting3-bromothiophene for 3-bromofuran, the title compound was prepared witha yield of 50%; mp 219°-220° C. C₁₁ H₁₅ NOS.0.5C₄ H₄ O₄ requires: C,58.4; H, 6.4; N, 5.2. Found: C, 58.2; H, 6.4; N, 5.2.

EXAMPLE 6 3-(5-Methylthienyl)quinuclidin-3-ol, 0.5 Fumarate 0.25 H₂ O

By essentially following the procedure in Example 1, substituting2-methylthiophene for thiophene, the title compound was prepared with ayield of 81%; mp 206°-206.5° C. C₁₂ H₁₇ NOS.0.5C₄ H₄ O₄ requires: C,58.8; H, 6.9; N, 4.9. Found: C, 59.1; H, 6.8; N, 4.9.

EXAMPLE 7 3-(3-Bromo-2-furyl)quinuclidin-3-ol, 0.5 Oxalate 0.5 H₂ O

By essentially following the procedure in Example 1, substituting3-bromofuran for thiophene and lithium-diisopropyl amide forn-buthyllithium, the title compound was prepared with a yield of 82%; mp225°-226° C. C₁₁ H₁₄ BrNO.0.5(COOH)₂ requires: C, 44.3; H, 4.9; N, 4.3.Found: C, 44.3; H, 4.6; N, 4.2.

EXAMPLE 8 3-(5-Ethyl-2-furyl)quinuclidin-3-ol, 0.5 Fumarate

By essentially following the procedure in Example 1, substituting2-ethylfuran for thiophene, the title compound was prepared with a yieldof 82%; mp 225°-226° C. C₁₃ H₁₉ NO₂.0.5C₄ H₄ O₄ requires: C, 64.5; H,7.6; N, 5.0. Found: C, 64.6; H, 7.6; N, 4.8.

EXAMPLE 9 3-(2-Benzofuryl)quinuclidin-3-ol, 0.5 Fumarate

By essentially following the procedure in Example 1, substitutingbenzofuran for thiophene, the title compound was prepared with a yieldof 79%; mp 203°-204° C. C₁₅ H₁₇ NO₂.0.5C₄ H₄ O₄ requires: C, 67.7; H,6.3; N, 4.6. Found: C, 67.5; H, 6.3; N, 4.6.

EXAMPLE 10 3-(2-Benzothienyl)quinuclidin-3-ol, Hydrochloride

By following the procedure in Example 1, substituting benzothiophene forthiophene, the title compound was prepared with a yield of 66%; mp219°-220° C. C₁₅ H₁₇ NOS.HCl requires: C, 60.9; H, 6.1; N, 4.7. Found:C, 61.0; H, 6.0; N, 4.7.

EXAMPLE 11 3-(3-Benzothienyl)quinuclidin-3-ol, Hydrochloride

By essentially following the procedure in Example 3, substituting3-bromobenzothiophene for 3-bromofuran, the title compound was preparedwith a yield of 82%; mp 216°-218° C. C₁₅ H₁₇ NOS.HCl .0.25H₂ O requires:C, 60.0; H, 6.2; N, 4.7. Found: C, 60.0; H, 6.2; N, 4.4.

EXAMPLE 12 3-(3-Benzoxazol-2-yl)quinuclidin-3-ol, Oxalate

By essentially following the procedure in Example 1, substitutingbenzoxazole for thiophene, the title compound was prepared with a yieldof 45%; mp 248°-249° C. C₁₄ H₁₆ N₂ O₂.0.5(COOH)₂ requires: C, 62.3; H,5.9; N, 9.7. Found: C, 62.4; H, 6.0; N, 9.6.

EXAMPLE 13 3-(Benzothiazol-2-yl)quinuclidin-3-ol, Hydrochloride

By essentially following the procedure in Example 1, substitutingbenzothiazole for thiophene, the title compound was prepared with ayield of 95%; mp 233°-235° C. C₁₄ H₁₆ N₂ OS.HCl requires: C, 56.6; H,5.8; N, 9.4. Found: C, 56.6; H, 5.8; N, 9.4.

EXAMPLE 14 3-(2-Thienyl)quinuclidin-2-ene, 0.5 Fumarate

3-(2-Thienyl)quinuclidin-3-ol (2.51 g, 11.98 mmol) prepared in Example 1was dissolved in concentrated formic acid (15 mL). The solution wasrefluxed for 2.5 h, alkalinized with 5M sodium hydroxide and extractedwith ether. The organic layer was dried over potassium carbonate andconcentrated in vacuo to yield 2.10 g (94%) of the product as a yellowoil. The product was converted into the fumarate and recrystallized fromMeOH/acetone/Et₂ O: mp 180°-182° C.; Rf 0.69 in CHCl₃ /MeOH (95:5) onalumina; C₁₁ H₁₃ NS.0.5C₄ H₄ O₄ requires: C, 62.6; H, 6.0; N, 5.6.Found: C, 62.2; H, 6.0; N, 5.6.

EXAMPLE 15 3-(2-Furyl)quinuclidin-2-ene, Oxalate

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(2-furyl)quinuclidin-3-ol prepared in Example 2,with a yield of 91%; mp 144°-144.5° C. C₁₁ H₁₃ NO.(COOH)₂ requires: C,58.9; H, 5.7; N, 5.3. Found: C, 58.6; H, 5.6; N, 5.1.

EXAMPLE 16 3-[3-Furyl)quinuclidin-2-ene, 0.5 Fumarate

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(3-furyl)quinuclidin-3-ol prepared in Example 3,with a yield of 96%; mp 181.5°-183.5° C. C₁₁ H₁₃ NO.0.5C₄ H₄ O₄requires: C, 66.9; H, 6.5; N, 6.0. Found: C, 66.6; H, 6.6; N, 5.9.

EXAMPLE 17 3-(5-Methyl-2-furyl)quinuclidin-2-ene, 0.5 Fumarate

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(5-methyl-2-furyl)quinuclidin-3-ol prepared inExample 4, with a yield of 93%; mp 159°-160° C. C₁₂ H₁₅ NO.0.5C₄ H₄ O₄requires: C, 68.0; H, 6.9; N, 5.7. Found: C, 67.8; H, 6.9; N, 5.6.

EXAMPLE 18 3-(3-Thienyl)quinuclidin-2-ene, 0.5 Fumarate

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(3-thienyl)quinuclidin-3-ol prepared in Example5, with a yield of 96%; mp 208°-210° C. C₁₁ H₁₃ NS.0.5C₄ H₄ O₄ requires:C, 62.6; H, 6.1; N, 5.6. Found: C, 62.8; H, 6.1; N 5.6.

EXAMPLE 19 3-(5-methyl-2-thienyl)quinuclidin-2-ene, 0.5 Fumarate

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(5-methylthienyl)quinuclidin-3-ol prepared inExample 6, with a yield of 96%; mp 196.5°-198° C. C₁₂ H₁₅ NS.0.5C₄ H₄ O₄requires: C, 63.8; H, 6.5; N, 5.3. Found: C, 63.6; H, 6.5; N, 5.2.

EXAMPLE 20 3-(3-Bromo-2-furyl)quinuclidin-2-ene, Oxalate, 0.75 H₂ O

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(3-bromo-2-furyl)quinuclidin-3-ol prepared inExample 7, with a yield of 86%; mp 148°-149° C. C₁₁ H₁₂BrNO.(COOH)₂.0.75H₂ O requires: C, 43.6; H, 4.3; N, 3.9. Found: C, 43.6;H, 3.9; N, 3.8.

EXAMPLE 21 3-(5-Ethyl-2-furyl)quinuclidin-2-ene, Fumarate 0.25 H₂ O

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(5-ethyl-2-furyl)quinuclidin-3-ol prepared inExample 8, with a yield of 96%; mp 81°-83° C. C₁₃ H₁₇ NO.C₄ H₄ O₄.0.25H₂O requires: C, 63.0; H, 6.7; N, 4.3. Found: C, 63.2; H, 6.5; N, 4.1.

EXAMPLE 22 3-(2-Benzofuryl)quinuclidin-2-ene, 0.5 Fumarate

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(2-benzofuryl)quinuclidin-3-ol prepared inExample 9, with a yield of 92%; mp 216°-217° C. C₁₅ H₁₅ NO.0.5C₄ H₄ O₄requires: C, 72.1; H, 6.0; N, 4.9. Found: C, 71.8; H, 6.0; N, 5.0.

EXAMPLE 23 3-(2-Benzothienyl)quinuclidin-2-ene, Hydrochloride

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(2-benzothienyl)quinuclidin-3-ol prepared inExample 10, with a yield of 80%; mp 250°-252° C. C₁₅ H₁₅ NS.HClrequires: C, 64.9; H, 5.8; N, 5.0. Found: C, 64.8; H, 5.8; N, 5.2.

EXAMPLE 24 3-(3-Benzothienyl)quinuclidin-2-ene, Hydrochloride

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(3-benzothienyl)quinuclidin-3-ol prepared inExample 11, with a yield of 84%; mp 185°-186° C. C₁₅ H₁₅ NS.HClrequires: C, 64.8; H, 5.8; 5.0. Found: C, 64.8; H, 5.8; N, 5.0.

EXAMPLE 25 3-(Benzothiazol-2-yl)quinuclidin-2-ene Hydrochloride

A mixture of 3-(benzothiazol-2-yl)quinuclidin-3-ol (0.55 g, 2.11 mmol)prepared in Example 13 and methanesulfonic acid (20 mL) was heated neatat 200° C. for 4 hours. Crushed ice (100 g) followed by 5M NaOH (untilpH 10 was reached) were carefully added to the reaction mixture.Extraction with ether (4×150 mL), drying (K₂ CO₃), filtration andconcentration in vacuo produced the product as a pale yellow solid. Thismaterial was purified by column chromatography on alumina using ether aseluent to yield 0.34 g (66%) of the title compound as a white solid. Thebase was converted into its hydrochloride and recrystallized frommethanol-ether. TLC Rf (free base on alumina)=0.42 (ether); mp196.5°-198.5° C. C₁₄ H₁₄ N₂ S.HCl requires: C, 60.3; H, 5.4; N, 10.0.Found: C, 60.4; H, 5.5; N, 10.2.

EXAMPLE 26 3-(Benzoxazol-2-yl)-quinuclidin-2-ene, Hydrochloride

By essentially following the procedure described in Example 25, the3-(benzoxazol-2-yl)quinuclidin-3-ol prepared in Example 12 gave thetitle compound with a yield of 56%; mp 199.5°-201.5° C. C₁₄ H₁₄ N₂ O.HClrequires: C, 64.0; H, 5.8; N, 10.7. Found: C, 64.0; H, 5.6; N 10.4.

EXAMPLE 27 3-(3-Phenylfuran-2-yl)quinuclidin-2-ene, Oxalate.0.4 H₂ O

A suspension of 3-(3-bromofuran-2-yl)quinuclidin-2-ene (486.2 mg, 19.1mmol) in 30 mL of dry dioxane, 67 mg (0.09 mmol) of PdCl₂ (PPh₃)₂, and702.5 mg (19.1 mmol) of tributylphenylstannane was refluxed under N₂ for36 hours. During the course of the reaction the colour changed fromyellow to black as Pd⁰ was formed. The reaction mixture was cooled,diluted with ether and filtered through a pad of Celite. Columnchromatography on silica using CHCl₃ /MeOH (85:15) as eluent yielded 250mg (52%) of the pure compound which was converted into the oxalate andrecrystallized from Et₂ O/MeOH; mp 184°-185° C.; Rf 0.4 in CHCl₃ /MeOH(85:15). C₁₇ H₁₇ NO.(COOH)₂.0.4H₂ O requires: C, 65.5; H, 5.7; N, 4.0.Found: C, 65.5; H, 5.6; N, 4.0.

EXAMPLE 28 3-(5-Trimethylstannyl-2-furyl)quinuclidin-2-ene

1.5M butyllithium in hexane (18.45 mL, 27.7 mmol) was added dropwiseunder nitrogen and at room temperature to a solution of3-(2-furyl)quinuclidin-2-ene (4.15 g, 23.7 mmol) in dry ether (50 mL).After refluxing for 10 min, the mixture was cooled to -70° C., and asolution of Me₃ SnCl (4.71 g; 23.68 mmol) in dry ether (20 mL) was addeddropwise. After the addition was complete, the mixture was warmed toroom temperature and allowed to stir for 2 hours. The reaction mixturewas quenched with saturated ammonium chloride (5 mL, added dropwise) andthe precipitate (LiCl) was filtered off and discarded. Concentration ofthe remaining solution followed by column chromatography of the soluteon silica using Et₂ O(NH₃)/MeOH (92:2) as eluent yielded 2.67 g (30%) ofthe title product. The pure compound was obtained followingrecrystallization from Et₂ O/hexane; Rf 0.5 in Et₂ O(NH₃)/MeOH (9:1) onsilica.

EXAMPLE 29 3-(5-Phenylfuran-2-yl)quinuclidin-2-ene, 0.5 Fumarate

A suspension of 3-(5-trimethylstannylfuran-2-yl)quinuclidin-2-ene (46.6mg, 0.125 mmol), prepared in Example 28, 4.38 mg (0.0062 mmol) of PdCl₂(PPh₃)₂, and iodobenzene (25.5 mg, 0.125 mmol) in dry THF (50 mL) wasrefluxed under N₂ for 24 hours. During the course of the reaction thecolour changed from yellow to black as Pd⁰ was formed. The reactionmixture was cooled, diluted with THF and filtered through a pad ofCelite. The product was purified on preparative TLC (silica) using Et₂O(NH₃)/MeOH (9:1) as eluent to yield 10 mg (32%) of the title compound.The title compound was converted into fumarate and recrystallized fromEt₂ O/MeOH: mp 189°-191° C.; Rf 0.59 in Et₂ O(NH₃)/MeOH (9:1). Anal. C₁₇H₁₇ NO.0.5C₄ H₄ O₄.H₂ O requires: C, 69.7; H, 5.8; N, 4.3. Found: C,69.8; H, 6.0; N, 4.0.

EXAMPLE 30 3-Tributylstannyl-quinuclidin-2-ene

A solution of 3-quinuclidinone (3.0 g, 24 mmol) in ether (30 mL) wasadded to a stirred suspension of 2,4,6-triisopropylbenzenesulfonylhydrazide (7.15 g, 24 mmol) in ether (30 mL). The reaction mixturebecame homogeneous and was stirred under nitrogen at room temperatureover night. The precipitate formed was filtered, and washed with etherto give 7.65 g of3-(2,4,6-triisopropylbenzenesulfonylhydrazone)quinuclidine (81%) (mp157°-160° C. R_(f) =0.60 (aluminium oxide, CHCl₃ +5% MeOH)). A solutionof 1.4M n-butyllithium in hexane (13.6 mL, 19.08 mmol) was addeddropwise during 15 min. to a stirred slurry of3-(2,4,6-triisopropylbenzenesulfonylhydrazone)quinuclidine (2.58 g, 6.36mmol) in TMEDA/hexane (70 mL, 1:1) under nitrogen at -78° C. Afterstirring for 1 hour at -78° C., the solution was allowed to warm to 0°C. The reaction mixture was cooled on an ice bath until the N₂ evolutionhad ceased (15 min.) and then treated with tributyltin chloride (4.14 g,12.7 mmol) in TMEDA/hexane (10 mL, 1:1). After stirring for 1.5 hour at0° C., solid NH₄ Cl was added and the mixture was filtrated andconcentrated under reduced pressure. The residue was purified bychromatography on aluminium oxide, first with a gradient elution (CHCl₃→CHCl₃ +5% MeOH) and then a second time with ether as eluent to yield1.85 g of the title compound (4.65 mmol, 73%); R_(f) (base) 0.61(aluminium oxide, CHCl₃ +2.5% MeOH).

EXAMPLE 31 3-(2-Methoxycarbonyl-5-furyl)-quinuclidin-2-ene, Oxalate

To a stirred solution of 3-tributylstannylquinuclidin-2-ene (3.43 g,8.61 mmol), prepared in Example 30, in dioxane (50 mL) were added2-bromo-5-methoxycarbonylfuran (1.76 g, 8.61 mmol) and PdCl₂ (PPh₃)₂(0.18 g, 0.26 mmol). The reaction mixture was refluxed for 5 days undernitrogen. The mixture was concentrated under reduced pressure. Theresidue was purified by chromatography on aluminium oxide with CHCl₃ aseluent and then on SiO₂ using CHCl₃ +10% MeOH as eluent and finally onaluminium oxide with ether as eluent. This provided 0.74 g of the titlecompound (3.19 mmol, 37%) as an oil. The base was converted into theoxalate and recrystallized from MeOH/ether: mp 162°-163° C. Rf(base)=0.42 (aluminium oxide, CHCl₃). C₁₃ H₁₅ NO₃.(COOH)₂ requires: C,55.7; H, 5.3; N, 4.3. Found: C, 55.6; H, 5.3; N, 4.2.

EXAMPLE 32 3-[5-(N-phenylcarbamoyl)-2-furyl]quinuclidin-2-ene, Oxalate

By essentially following the procedure described in Example 31,substituting 2-(N-phenylcarbamoyl)furan for2-bromo-5-methoxycarbonylfuran, the title compound was prepared in ayield of 41%; mp 238°-239° C. C₁₈ H₁₈ N₂ O₂.(COOH)₂ requires: C, 62.5;H, 5.2; N, 7.3. Found: C, 62.3; H, 5.3; N, 7.0.

EXAMPLE 33 3-(5-Bromo-2-benzofuryl)quinuclidin-3-ol

3-Ethynyl-3-hydroxyquinuclidine (3.0 g, 19.8 mmol) and 2,6-dibromophenol(5.0 g, 19.8 mmol) were added to a stirred suspension of copper(I)oxide(1.7 g, 11.9 mmol) in dry pyridine (50 mL). The mixture was refluxedunder N₂ for 15 hours. The solvent was evaporated and the residue wasdissolved in CHCl₃ and extracted with 1M NaOH. The organic phase wasdried (K₂ CO₃) and concentrated under reduced pressure. The residue waspurified by chromatography on aluminium oxide with gradient elutionusing CHCl₃ →CHCl₃ +5% MeOH to yield 1.17 g of product. The solidresidue was recrystallized from CHCl₃ to yield 0.79 g (12%) of the titlecompound. Mp 244°-245° C., Rf 0.43 (Al₂ O₃, CHCl₃ +5% MeOH).

EXAMPLE 34 3-(5-Bromo-2-benzofuryl)quinuclidin-2-ene

By essentially following the procedure in Example 14, the title compoundwas prepared from the 3-(5-bromo-2-benzofuryl)quinuclidin-3-ol preparedin Example 33.

EXAMPLE 35 3-(5-Butyl-2-furyl)quinuclidin-3-ol

The title compound was prepared by essentially following the procedurein Example 1, substituting 2-butylfuran for thiophene; mp 94°-96° C.

EXAMPLE 36 3-(5-Butyl-2-furyl)quinuclidin-2-ene, Oxalate

The title compound was prepared from the3-(5-butyl-2-furyl)quinuclidin-3-ol prepared in Example 35 byessentially following the procedure in Example 14; mp 163°-164° C.

EXAMPLE 37 3-(5-Acetyl-2-furyl)quinuclidin-2-ene, Oxalate

The title compound was prepared by following an analogous procedure tothe one described in Example 28; mp 166°-167° C.

EXAMPLE 38 3-(4-Acetyl-2-furyl)quinuclidin-2-ene, Oxalate

The title compound was prepared by following an analogous procedure tothe one described in Example 27; mp 175°-176° C.

EXAMPLE 39 3-(4-Phenyl-2-furyl)quinuclidin-2-ene, Oxalate

The title compound was prepared by following an analogous procedure tothe one described in Example 27; mp 177°-179° C.

EXAMPLE 40 3-(5-Acetyl-2-thienyl)quinuclidin-2-ene, Oxalate

The title compound was prepared by essentially following the procedurein Example 31; mp 184°-185° C.

EXAMPLE 41 3-(5-Formyl-2-thienyl)quinuclidin-2-ene, Oxalate

The title compound was prepared by essentially following the procedurein Example 31; mp 181°-182° C.

EXAMPLE 42 3-(5-Formyl-7-methoxy-2-benzofuryl)quinuclidin-2-ene, Oxalate

The title compound was prepared by essentially following the procedurein Example 33 and Example 14; mp 220° C. (decomp.).

EXAMPLE 43 3-(5-Hydroxymethyl -7-methoxy-2-benzofuryl)quinuclidin-2-ene,Oxalate

The title compound was prepared from3-(5-formyl-7-methoxy-2-benzofuryl)quinuclidin-2-ene by a reductionusing NaBH₄ in MeOH; mp 203°-204° C.

EXAMPLE 44 3-(7-Hydroxymethyl-5-iodo-2-benzofuryl)quinuclidin-2-ene, 0.5Oxalate

The title compound was prepared by following procedures analogous to theones described in Example 33, Example 14 and Example 43; mp 233°-235° C.

EXAMPLE 45 3-(7-iodo-5-nitro-2-benzofuryl)quinuclidin-2-ene, Oxalate

The title compound was prepared by essentially following the proceduresin Example 33 and Example 14; mp 255°-260° C. (decomp.).

EXAMPLE 46 3-(5-cyano-7-iodo-2-benzofuryl)quinuclidin-2-ene, Oxalate

The title compound was prepared by essentially following the proceduresin Example 33 and Example 14; mp 255°-265° C. (decomp.).

PREPARATION OF PHARMACEUTICAL COMPOSITIONS

    ______________________________________                                        EXAMPLE A: preparation of tablets                                             Ingredients             mg/tablet                                             ______________________________________                                        1.      Compound in Ex. 27   2.0                                              2.      Cellulose, microcrystalline                                                                       57.0                                              3.      Calcium hydrogen phosphate                                                                        15.0                                              4.      Sodium starch glycolate                                                                            5.0                                              5.      Silicon dioxide, colloidal                                                                        0.25                                              6.      Magnesium stearate  0.75                                                                          80.0 mg                                           ______________________________________                                    

The title compound in Example 27 is mixed with ingredients 2, 3, 4 and 5for about 10 minutes. The magnesium stearate is then added, theresultant mixture being mixed for about 5 minutes and then compressedinto tablet form with or without film-coating.

    ______________________________________                                        EXAMPLE B: preparation of capsules                                                    Ingredients    mg/capsule                                             ______________________________________                                        1.        Compound in Ex. 21                                                                              2                                                 2.        Lactose          186                                                3.        Corn Starch       20                                                4.        Talc              15                                                5.        Magnesium stearate                                                                              2                                                                            225 mg                                             ______________________________________                                    

The title compound in Example 21 is mixed with ingredients 2 and 3 andthen milled. The resulting mixture is mixed with ingredients 4 and 5 andthen filled into capsules of appropriate size.

BIOLOGICAL EVALUATION

The biological activity of compounds of the present invention was testedusing several tests.

Receptor Binding Assay

The affinity of the compounds was determined for muscarinic receptorsubtypes in the cerebral cortex, parotid gland, heart and bladderpreparations from guinea pig by their ability to displace radiolabeledquinuclidinyl benzilate, a well-known muscarinic receptor antagonist.The experimental conditions are described in detail by L. Nilvebrant andB. Sparf in Eur. J. Pharmacol. 1986, 123, 133. The results are presentedin Table 1 below.

Functional In Vitro Studies

Male guinea pigs, weighing about 300 g, were killed by a blow on theneck and exsanguinated. Smooth muscle strips of the urinary bladder andileum (longitudinal muscle only) were dissected in a Krebs-Henseleitsolution (pH 7.4). The strip preparations were then vertically mountedbetween two hooks in thermostatically controlled (37° C.) organ baths (5mL). One of the hooks was adjustable and connected to a force transducer(FT 03, Grass Instruments). The Krebs-Henseleit solution wascontinuously bubbled with carbogen gas (93.5% O₂ /6.5% CO₂) to maintainpH at 7.4. Isometric tension was recorded by a Grass Polygraph (model79D). A resting tension of approximately 5 mN was initially applied oneach muscle strip and the preparations were allowed to stabilize for atleast 45 min. The resting tension was repeatedly adjusted and thepreparations were washed several times during the stabilization period.

The urinary bladder strips were used for evaluation of antimuscarinicactivity and the ileal preparations for studies of muscarinic activity.Carbachol (carbamylcholine chloride) was used as the standard agonist.Concentration-response curves to agonists were generated either by thecumulative dose-response technique (bladder strip) or by the addition ofsingle agonist concentrations (ileal preparations). In the latter case,the preparations were washed and allowed to rest between eachconcentration of agonist. EC₅₀ values were graphically determined.

In studies of antagonism, a control concentration-response curve tocarbachol was generated by cumulative addition of carbachol to thebladder strip (i.e., stepwise increase of the agonist concentrationuntil the maximal contractile response was reached), followed by washingout and a resting period of at least 15 min. before a fix concentrationof the test compound (antagonist) was added to the organ-bath. After 60min. of incubation, a second cumulative concentration-response curve tocarbachol was generated. Responses were expressed as percent of themaximal response to carbachol. EC₅₀ -values for carbachol in the absence(control) and presence of antagonist were graphically derived and doseratios (r) were calculated. Dissociation constants, K_(b), for theantagonists were then calculated using the following equation (1), where[A] is the concentration of test compound.

    K.sub.b =[A]/r-1                                           (1)

The results of the above described functional in vitro studies arepresented in Table 1 below together with the results from the receptorbinding assay described further above; the data for the agonistic effecton ileum is in relation to maximal carbachol response (E_(max)).

                  TABLE 1                                                         ______________________________________                                        Com-                                                                          pound Cortex  Heart    Parotis                                                                             Bladder                                          Ex.   (nM)    (nM)     (nM)  (nM)   K.sub.b                                                                             Ileum                               ______________________________________                                        1     12000   >23000   49000 45000  40000                                     3                                   87000                                     4                                   1200                                      5                                   84000                                     6                                   23000                                     7     4900    10000    20000 12000  11000                                     8                                   6700                                      9                                   720                                       10                                  3700                                      11                                  4300                                      12                                  3900                                      13    1200    3000     3800  8100   4200                                      14                                  1100                                      15                                  550                                       16                                  3400                                      17                                  61                                        18    710     1700     2600  3700   2000                                      19                                  320   10% at                                                                        500 μM                           21                                  31                                        22                                  33                                        23                                  660                                       24                                  170                                       25                                  810                                       26    170     600      1100  760    190                                       27                                  2.7                                       29                                  1020                                      31                                  2600  21% at                                                                        500 μM                           ______________________________________                                    

From Table 1 above, the substantial increase in antagonism obtained byintroducing the double bond into the quiniclidine ring is readily seenwhen comparing the data for the quinuclidinol compounds 1 to 13 with thedata for the corresponding quinuclidinenes 14 to 26.

We claim:
 1. A compound of the general Formula I: ##STR13## wherein R is a group of the general Formula II or III: ##STR14## where X¹ represents oxygen or sulphur and Y¹ and Z¹ both represent carbon;one of X², Y² and Z² represents oxygen or sulphur and the other two both represent carbon or one represents nitrogen and the other represents carbon, and the dotted line in Formula III represents an optional additional carbon-carbon or carbon-nitrogen bond; A¹, A², A³ and A⁴ each represent carbon or, when one of X², Y² and Z² represents oxygen or sulphur and the other two both represent carbon, one of A¹, A², A³ and A⁴ may represent nitrogen and the others carbon; R¹, R² and R³ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyloxy, C₂₋₁₀ alkynyloxy, C₃₋₁₀ cycloalkyloxy, C₅₋₁₀ cycloalkenyloxy, C₄₋₁₀ cycloalkylalkoxy, C₆₋₁₀ cycloalkylalkenyloxy, hydroxy, hydroxy-C₁₋₁₀ alkyl, or (CH₂)_(n) Ar, where Ar is an optionally substituted aryl selected from the group consisting of phenyl and naphthyl or heteroaryl, the latter containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen and being selected from the group consisting of thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, pyridine, benzofuran, isobenzofuran, benzothiazole, benzothiophene, indole, isoindole, oxadiazole and benzooxazole and n is an integer 0 to 10; and R⁴ and R⁵ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, halogen or (CH_(m))_(n) B, wherein (CH_(m))_(n), in which n is as defined above and m independently is an integer 0 to 2, represents a bond or a straight or branched, saturated or unsaturated hydrocarbon chain and B represents Ar (as defined above), COR⁶, COOR⁶, CON(R⁶)₂, N(R⁶)₂, OR⁶, CN, NO₂, C═NOR⁶, OCOR⁶, N(R⁶)COR⁶, C(R⁶)₂ OR⁶, OCOC(OH)(R⁶)₂ or trifluoromethyl where R⁶ independently represents hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, (CH₂)_(n) Ar or a bi- or tricyclic ring system, wherein Ar and n are as defined above; or R⁴ and R⁵ are interconnected to complete a saturated or unsaturated ring which may contain 1 or 2 hetero atoms; with the proviso that when R represents a group of Formula II and R¹, R² and R³ each are hydrogen, R is other than 2-furyl, 4-methyl-2-furyl and 5-methyl-2-furyl; and physiologically acceptable salts thereof.
 2. A compound according to claim 1, wherein R¹, R² and R³ each represent hydrogen.
 3. A compound according to claim 1 or 2, wherein R is a group of Formula II where X¹ represents oxygen or sulphur and Y¹ and Z¹ are carbon, or a group of Formula III where A¹ to A⁴ each represent carbon and one of X², Y² and Z² represents oxygen or sulphur and the others represent carbon.
 4. A compound according to claim 3, wherein R is a group of Formula II and X¹ represents oxygen, or R is a group of Formula III and said one of X², Y² and Z² represents oxygen.
 5. A compound according to claim 4, wherein R⁴ and R⁵ are selected from hydrogen, C₁₋₁₀ alkyl, optionally substituted aryl or heteroaryl and (CH_(m))_(n) B, where (CH_(m))_(n) is methylene, ethylene, allylene, vinylene or acetylene and B is N(R⁶)₂, OR⁶, C═NOH, OCOR⁶, N(R⁶)COR⁶ or C(R⁶)₂ OR⁶ where R⁶ independently is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or optionally substituted phenyl or furyl.
 6. A compound according to claim 5, wherein one of R⁴ and R⁵ represents hydrogen and the other represents C₁₋₁₀ alkyl or optionally substituted aryl selected from the group consisting of phenyl and naphthyl, preferably C₁₋₆ alkyl or optionally substituted phenyl.
 7. A compound according to claim 1 selected from:3-(2-furyl)quinuclidin-2-ene; 3-(3-furyl)quinuclidin-2-ene; 3-(5-ethyl-2-furyl)quinuclidin-2-ene; 3-(3-bromo-2-furyl)quinuclidin-2-ene; 3-(3-thienyl)quinuclidin-2-ene; 3-(2-thienyl)quinuclidin-2-ene; 3-(5-methyl-2-furyl)quinuclidin-2-ene; 3-(3-phenyl-2-furyl)quinuclidin-2-ene; 3-(5-methyl-2-thienyl)quinuclidin-2-ene; 3-(5-phenyl -2-furyl)quinuclidin-2-ene; 3-(3-methyl-2-furyl)quinuclidin-2-ene; 3-(5-methoxycarbonyl-2-furyl)-quinuclidin-2-ene; 3-(2-benzofuryl)quinuclidin-2-ene; 3-(5-bromo-2-benzofuryl)-quinuclidin-2-ene; 3-(2-benzothienyl)quinuclidin-2-ene; 3-(3-benzothienyl)quinuclidin-2-ene; 3-(benzothiazol-2-yl)quinuclidin-2-ene; 3-[5-(N-phenylcarbamoyl)-2-furyl]-quinuclidin-2-ene; 3-(benzoxazol-2-yl)quinuclidin-2-ene; 3-(5-butyl-2-furyl)quinuclidin-2-ene; 3-(5-acetyl-2-furyl)quinuclidin-2-ene; 3-(4-acetyl-2-furyl)quinuclidin-2-ene; 3-(4-phenyl-2-furyl)quinuclidin-2-ene; 3-(5-acetyl-2-thienyl)quinuclidin-2-ene; 3-(5-formyl-2-thienyl)quinuclidin-2-ene; 3-(5-formyl-7-methoxy-2-benzofuryl)quinuclidin-2-ene; 3-(5-hydroxymethyl-7-methoxy-2-benzofuryl)quinuclidin-2ene; 3-(7-hydroxymethyl-5-iodo-2-benzofuryl)quinuclidin-2-ene; 3-(7-iodo-5-nitro-2-benzofuryl)quinuclidin-2-ene; 3-(5-cyano-7-iodo-2-benzofuryl)quinuclidin-2-ene;and physiologically acceptable salts thereof.
 8. A pharmaceutical composition comprising a compound of the general Formula I: ##STR15## wherein R is a group of the general Formula II or III: ##STR16## where X¹ represents oxygen or sulphur and Y¹ and Z¹ both represent carbon;one of X², Y² and Z² represents oxygen or sulphur and the other two both represent carbon or one represents nitrogen and the other represents carbon, and the dotted line in Formula III represents an optional additional carbon-carbon or carbon-nitrogen bond; A¹, A², A³ and A⁴ each represent carbon or, when one of X², Y² and Z² represents oxygen or sulphur and the other two both represent carbon, one of A¹, A², A³ and A⁴ may represent nitrogen and the others carbon; R¹, R² and R³ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyloxy, C₂₋₁₀ alkynyloxy, C₃₋₁₀ cycloalkyloxy, C₅₋₁₀ cycloalkenyloxy, C₄₋₁₀ cycloalkylalkoxy, C₆₋₁₀ cycloalkylalkenyloxy, hydroxy, hydroxy-C₁₋₁₀ alkyl, or (CH₂)_(n) Ar, where Ar is an optionally substituted aryl selected from the group consisting of phenyl and naphthyl or heteroaryl, the latter containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen and being selected from the group consisting of thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, pyridine, benzofuran, isobenzofuran, benzothiazole, benzothiophene, indole, isoindole, oxadiazole and benzooxazole and n is an integer 0 to 10; and R⁴ and R⁵ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, halogen or (CH_(m))_(n) B, wherein (CH_(m))_(n), in which n is as defined above and m independently is an integer 0 to 2, represents a bond or a straight or branched, saturated or unsaturated hydrocarbon chain and B represents Ar (as defined above), COR⁶, COOR⁶, CON(R⁶)₂, N(R⁶)₂, OR⁶, CN, NO₂, C═NOR⁶, OCOR⁶, N(R⁶)COR⁶, C(R⁶)₂ OR⁶, OCOC(OH) (R⁶)₂ or trifluoromethyl, where R⁶ independently represents hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, (CH₂)_(n) Ar or a bi- or tricyclic ring system, wherein Ar and n are as defined above; or R⁴ and R⁵ are interconnected to complete a saturated or unsaturated ring which may contain 1 or 2 hetero atoms; in association with a pharmaceutically acceptable carrier.
 9. A process for the preparation of a compound of the general Formula I as defined in claim 1, which process comprises:(a) dehydrating a compound of the general Formula IV: ##STR17## wherein R, R¹, R² and R³ are as defined in claim 1; or (b) for the preparation of a compound of Formula I wherein R⁴ and R⁵ are as defined in claim 1 except that R⁵ is other than hydrogen, reacting, in the presence of a metal catalyst, a compound of the general Formula V or VI: ##STR18## with a compound R⁸ -D, wherein X¹, Y¹, Z¹, X², Y², Z² and R⁴ are as defined in claim 1, D is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, (CH₂)_(n) Ar or (CH_(m))_(n) B, where Ar, n, m and B are as defined in claim 1, and one of R⁷ and R⁸ represents halogen, triflate or mesylate and the other represents a group selected from Sn(Alk)₃, Si(Alk)₃, ZnHal, Al(R⁹)₂, TlX₂, HgX, and B(OR⁹)₂, where Alk is alkyl of from 1 to 10 carbon atoms, Hal is halogen, X is halogen, acetate or trifluoroacetate, and R⁹ is hydrogen or Alk, or R⁷ represents halogen, triflate or mesylate and R⁸ -D is C₂₋₁₀ alk-1-yn; c) for the preparation of a compound of Formula I wherein R⁴ and R⁵ are as defined in claim 1 except that R⁵ is other than hydrogen, generating the carbanion of a compound of the general Formula VII or VIII: ##STR19## wherein X¹, Y¹, Z¹, X², Y², Z² and R⁴ are as defined in claim 1, and R¹⁰ represents hydrogen or halogen, and reacting the carbanion formed with an electrophilic reagent capable of forming the desired substitutent R⁵ ; (d) reacting, in the presence of a metal catalyst, a compound of the general Formula IX: ##STR20## with a compound R--E, wherein R, R¹, R² and R³ are as defined in claim 1, and one of R¹¹ and E represents halogen, triflate or mesylate and the other represents a group selected from Sn(Alk)₃, Si(Alk)₃, ZnHal, Al(R⁹)₂, TlX₂, HgX and B(OR⁹)₂, where Alk is alkyl of from 1 to 10 carbon atoms, Hal is halogen, X is halogen, acetate or trifluoroacetate, and R⁹ is hydrogen or Alk, (e) for the preparation of compounds of Formula I, wherein R is a group Formula III, in which A¹ to A⁴ each are carbon or one of A¹ to A⁴ are nitrogen and the others are carbon, X² is oxygen or sulphur and Y² and Z² both are carbon, reacting a compound or intermediate of the general Formula X: ##STR21## wherein R¹, R² and R³ are as defined in claim 1, with a compound of the general Formula XI: ##STR22## wherein R⁴ and R⁵ are as defined in claim 1, Hal represents halogen, X^(2a) represents oxygen or sulphur, and A^(1a) to A^(4a) each represent carbon or one of A^(1a) to A^(4a) represent nitrogen and the others represent carbon; (f) for the preparation of compounds of Formula I, wherein R is a group Formula III, in which A¹ to A⁴ each are carbon or one of A¹ to A⁴ are nitrogen and the others are carbon, X² is oxygen or sulphur and Y² and Z² both are carbon, reacting a compound or intermediate of the general Formula XII: ##STR23## wherein R¹, R² and R³ are as defined in claim 1, with a compound of Formula XI as defined in process e) above, and then dehydrating the product formed; (g) in a compound of Formula I, converting a group R⁴ or R⁵ into another group R⁴ or R⁵ ; and, if desired, forming a physiologically acceptable salt with an organic or inorganic acid.
 10. A compound of the general Formula IV: ##STR24## wherein R is a group of the general Formula II or III: ##STR25## where X¹ represents oxygen or sulphur and Y¹ and Z¹ both represent carbon;one of X², Y² and Z² represents oxygen or sulphur and the other two both represent carbon or one represents nitrogen and the other represents carbon, and the dotted line in Formula III represents an optional additional carbon-carbon or carbon-nitrogen bond; A¹, A², A³ and A⁴ each represent carbon or, when one of X², Y² and Z² represents oxygen or sulphur and the other two both represent carbon, one of A¹, A², A³ and A⁴ may represent nitrogen and the others carbon; R¹, R² and R³ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyloxy, C₂₋₁₀ alkynyloxy, C₃₋₁₀ cycloalkyloxy, C₅₋₁₀ cycloalkenyloxy, C₄₋₁₀ cycloalkylalkoxy, C₆₋₁₀ cycloalkylalkenyloxy, hydroxy, hydroxy-C₁₋₁₀ alkyl, or (CH₂)_(n) Ar, where Ar is an optionally substituted aryl selected from the group consisting of phenyl and naphthyl or heteroaryl, the latter containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen and being selected from the group consisting of thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, pyridine, benzofuran, isobenzofuran, benzothiazole, benzothiophene, indole, isoindole, oxadiazole and benzooxazole and n is an integer 0 to 10; and R⁴ and R⁵ independently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, halogen or (CH_(m))_(n) B, wherein (CH_(m))_(n), in which n is as defined above and m independently is an integer 0 to 2, represents a bond or a straight or branched, saturated or unsaturated hydrocarbon chain and B represents Ar (as defined above), COR⁶, COOR⁶, CON(R⁶)₂, N(R⁶)₂, OR⁶, CN, NO₂, C═NOR⁶, OCOR⁶, N(R⁶)COR⁶, C(R⁶)₂ OR⁶, OCOC(OH) (R⁶)₂ or trifluoromethyl, where R⁶ independently represents hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, C₄₋₁₀ cycloalkylalkyl, C₆₋₁₀ cycloalkylalkenyl, (CH₂)_(n) Ar or a bi- or tricyclic ring system, wherein Ar and n are as defined above; or R⁴ and R⁵ are interconnected to complete a saturated or unsaturated ring which may contain 1 or 2 heteroatoms; with the proviso that when R represents a group of Formula II and R¹, R² and R³ each are hydrogen, R is other than 2-furyl, 4-methyl-2-furyl and 5-methyl-2-furyl;and salts thereof.
 11. A method for the treatment and/or prophylaxis of a disease or disorder, wherein said disease or disorder is selected from the group consisting of dementia, spastic states of the gastrointestinal tract, peptic ulcers, incontinence and bradycardia, comprising:administering to a patient, in need thereof, an effective amount of a compound, as defined in claim
 1. 